Johns Hopkins University

NIH Research Projects · FY 2026 · 2024-07

Project Summary Behavioral control is a fundamental component of executive control and requires the ability to suppress actions, thoughts, and desires. Deficits in behavioral control are thought to be at the core of many public health concerns in the United States. Nevertheless, currently little is known about the mechanisms underlying behavioral control and what leads to failures of control. Response inhibition and self-control, two key aspects of behavioral control, are often hypothesized to be the result of a uniform neuronal mechanism for impulse control, but they have typically been studied independently, and it is possible that the brain contains separate neuronal mechanisms for motor and motivational control. Neuroimaging and lesion studies in humans have implicated a network of prefrontal regions in self-control, as well inhibitory motor control, including frontal eye field (FEF), supplementary eye field (SEF), pre-supplementary motor area (preSMA), dorsolateral prefrontal cortex (DLPFC), and ventrolateral prefrontal cortex (VLPFC). However, it is not clear if the neuronal circuits of motor control and self-control are identical or separate. In our proposed experiments, we will investigate prefrontal mechanisms for self-control and response inhibition in these areas. Comparing the mechanisms for both types of control requires tasks that allow identification of signals involved in response inhibition and self-control. We will train monkeys both in a novel self-control task developed by us (requiring motivational control) and in the classic stop signal task (requiring motor control). This will allow us to identify circuit level mechanisms of self-control and response inhibition. Our Aim 1 is to determine if the neural mechanisms of response inhibition and self-control in prefrontal cortex are shared or distinct. We will record the neural activity of multiple neurons in FEF, SEF, preSMA, DLPFC and VLPFC. By testing identical sets of prefrontal neurons in both tasks, we will identify neuronal activity underlying each control mechanism and determine if identical or separate circuits are responsible for both forms of executive control. Our Aim 2 is to determine if different areas in prefrontal cortex causally contribute to response inhibition and self- control. Preliminary data show that inactivation of SEF by cooling will bias behavioral outcomes toward failures of self-control. This indicates a causal role of SEF in self-control. We will systematically test the causal role of FEF, SEF, preSMA, DLPFC and VLPFC in response inhibition and self-control, by inactivating each of these areas and observe behavior in the delayed gratification and stop signal tasks. Inactivating one area, while simultaneous recording in other areas will determine if neuronal representations of response inhibition or self-control are causally dependent on activity in other parts of the network of prefrontal regions.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Immunoglobulin E (IgE) binds with high affinity to its receptor, FCeR1, found on the surface of basophils and mast cells. When an antigen binds to receptor bound IgE, it can lead to IgE receptor cross-linking and activation of basophils and mast cells. In this case, the antigen is subcategorized as an allergen. Thus, IgE is a pivotal molecule in the initiation of allergic reaction in a wide range of tissue. The IgE-dependent activation of basophils leads to the release of granular mediators and, also, to the production of Th2 inflammatory cytokines, IL4/5/13. Recent work has revealed a novel, allergen independent mechanism by which IgE, bound to its receptor, can lead to basophil activation resulting in greater IL4/13 production compared to standard IgE- dependent activation. The mechanism of this allergen-independent activation involves the sugar-binding protein Galectin-3 (Gal-3), which has been shown to bind directly to IgE. The data reveal that when a Gal-3 bearing cell physically comes into contact with a basophil, it leads to strong basophil activation. However, the parameters of this interaction remain poorly defined. I hypothesize that Gal-3 interacts with IgE independently of allergen specificity due to IgE’s variable glycosylation patterns, and that such glycosylation patterns may differ between allergic and non-allergic subjects. IgE with more N-glycan sugars will interact better with Gal-3 while IgE with more sialic acid will not interact as well. My first aim is to compare Gal-3 with standard IgE- dependent activation of basophils sensitized by serum from either allergic or non-allergic patients. My second aim examines the hypothesis that the affinity of Gal-3 for IgE is based on the presence of N-glycan structures and that this binding can be masked by terminal sialic acid residues. I will treat both whole cells and purified IgE with glycan modifying enzymes and quantify the Gal-3-induced cytokine production in basophils. My preliminary data shows that neuraminidase treatment, to remove terminal sialic acid residues, of whole basophils primed with IL-3 and bearing IgE augments Th2 cytokine production when placed in co-culture with Gal-3 bearing cells. The results of the study are expected to provide insight into a novel mechanism of allergen independent IgE activation and should prompt investigation to correlate it with clinical relevance.

NIH Research Projects · FY 2026 · 2024-07

Investigating Germline Sex Determination Establishing sex-specific germ cell identity is critical for development of sperm and eggs and perpetuation of the species. Cells are initially specified as primordial germ cells (PGCs), and then germline sex determination establishes a male or female germline identity. While sex determination is understood in the somatic cells of some animals, how germline sexual identity is established is largely unknown. In most animals, germline sex determination is regulated by signals from the surrounding somatic gonad. However, in some animals, like humans and Drosophila, the germ cell’s sex chromosome constitution is also important. Thus, the sex of the soma and germline must match for proper gametogenesis to proceed. How somatic signals interface with germ cell autonomous cues to achieve proper sex determination is also unknown. Many aspects of germ cell identity are regulated at the post-transcriptional level. The RNA binding protein Sex lethal (Sxl) is activated in XX germ cells and is necessary and sufficient for germline sex determination in Drosophila, but little is known about how it acts to control this process. Further, a germ cell-specific transcriptional program must also be established in order for Sxl to influence this program in a sex-specific manner. Lastly, Sxl in the germline must combine with signals from the soma to determine germline sexual identity. Recently, we have made two important discoveries that illuminate these processes. First, an important signal from the soma that promotes male germline identity acts through the Jak/Stat pathway. As this pathway is also used to regulate development of the somatic gonad in both sexes, Sxl acts in female germ cells to block the Jak/Stat pathway and preserve female germline identity. Second, we have discovered a new tudor-domain protein, Tdrd5l, that is important for male identity in the germline and is a putative target for repression by Sxl in the female germline. Tdrd5l defines a novel germline granule, the “Tdrd5l body” and our preliminary data indicates that Tdrd5l regulates germline gene expression at the post-transcriptional level. We propose to use Tdrd5l as a model for understanding the regulation of gene expression in the germline and to investigate the mechanism of action of the “Tdrd5l body”.

NIH Research Projects · FY 2025 · 2024-07

Project Summary: F99 Phase Primary hereditary microcephaly, gray matter heterotopia, autism spectrum disorder, bipolar disorder, and schizophrenia affect millions of individuals worldwide and have all been linked to improper neurodevelopment, a tightly regulated process where temporal and spatial regulation of the cell cycle is integral to the production of the right number and type of cells in the brain. Temporal dysregulation such as significant mitotic delay in cortical progenitors has been known to result in Tp53 induced apoptosis in response to activation of the Mitotic Surveillance Pathway (MSP), depleting the neural progenitor pool and reducing the number of neurons produced. Spatial dysregulation, such as alterations of location where progenitors divide within the developing cortex, has been shown to alter cortical organization. Mutations in genes involved in cilia biogenesis, affecting neural progenitor signaling, have been shown to result in an array of conditions such as macrocephaly and polymicrogyria. I use multiple mutant mouse models that affect the centrosome-related functions of progenitor division speed, cilia production, and neocortical localization to better understand how dysregulation of those processes affect cell fate and cortical organization both when the MSP is active and inactive. The amount of time mitosis is delayed in my models varies depending on the allele that is knocked out, with a subset of the mitotically delayed models additionally having their progenitors delocalized and spread throughout the developing cortex. I will use these mouse models to: Aim 1A: Characterize how these genetic manipulations affect cortical development using gross and immunofluorescent analysis techniques. Aim 1B: Perform single-cell RNA sequencing in conjunction with CFSE and EdU labeling, elucidating the transcriptome of all cycling progenitors (EdU), and progenitors based on the number of divisions it has gone through since they were in contact with the ventricular surface (CFSE). Aim 1C: Investigate how location of progenitors influence gene expression by using the spatial transcriptomic method, MERFISH. Thus, I hypothesize that the centrosome-related functions of progenitor division speed, cilia production, and localization ensure spatiotemporal regulation of corticogenesis, and when perturbed, uniquely change neural progenitor expression profiles, altering fate specification and cortical organization. Having both active and inactive MSP models will allow the investigation of progenitor fate in two different directions. With an active MSP, the time progenitors are delayed in mitosis will be linked with the number and type of progenitors that are able to avoid MSP activation and differentiate, illuminating which mature neuron types are produced for a given mitotic delay time. With the inactive MSP models, all progenitors will be able to proliferate and differentiate. I will be able to link alterations in time and location of progenitor division to changes in the neural progenitor pool population and the resulting number, type, and destination of mature neurons. By using transcriptomic methods, I will additionally be able to see how the transcriptome of progenitors change as a result of cilia loss, mitotic delay, and centrosome loss.

NIH Research Projects · FY 2026 · 2024-07

Syphilis rates in the United States (US) have reached their highest levels in decades. In 2023, over 209,000 new syphilis diagnoses were reported – surpassing the previous peak in 1990 and more than doubling over the past five years alone. The rate of congenital syphilis has increased by eight-fold since 2011 – reaching one in every 1,300 US births in 2021. The surge in syphilis cases is evident across the US, with highest concentration in urban areas. Amidst declining public health budgets, local policymakers face the challenge of identifying the most efficient and cost-effective ways to invest in these existing tools to alter the trajectory of the US syphilis epidemic. Innovations in syphilis prevention and diagnoses, such as doxycycline for post-exposure prophylaxis ("doxy-PEP") and new diagnostics like point-of-care (POC) or at-home testing, hold promise in reducing syphilis incidence. Efforts to curb new infections require multifactorial approaches addressing underlying transmission drivers. To reverse syphilis trends, it is critical to identify the most efficient use of limited public health resources, recognizing that a one-size-fits-all solution may not be suitable for all US cities. Mathematical models of infectious disease dynamics serve as powerful tools for forecasting the impact of infection control strategies. Despite extensive applications in studying HIV and other sexually transmitted infections, there is a marked lack of modeling of US syphilis over the last decade. The absence of representative models for the US syphilis epidemic hinders the effective formulation of evidence-based policy to control further spread of infections. In this proposal, we plan to develop a novel suite of local-level syphilis epidemiologic and economic models (LSEEM) across 40 US cities with the highest syphilis diagnosis rates. The model will consider syphilis transmission, progression, HIV co-infection, STI care engagement dynamics, and age. In Aim 1, we will assess the potential impact of scaling up "existing" syphilis control interventions, focusing on increased testing, expanded partner tracing, and faster treatment initiation. Our objective is to provide achievable, cost-effective, and practical suggestions applicable to local jurisdictions. Aim 2 involves evaluating the scale-up of "emerging" diagnostics and biomedical interventions under various assumptions concerning population coverage and costs. Our goal is to determine the conditions under which these interventions would be cost-effective when entering the market. Finally, in Aim 3, we will develop a user-friendly online toolkit to enable decision-makers at local, state, and national levels to obtain customized projections of the impact from diagnostic or biomedical prevention interventions. This tool will aid in translating data into evidence-based policy-making, bridging a critical gap and providing a roadmap for informing future syphilis control interventions. Collaborating with the health departments of New York City, Baltimore City, and New York State will further facilitate translation of the results into actionable policies.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY The purpose of this K99/R00 Pathway to Independence Award is to support Dr. Lauren Zalla as she transitions into an independent research career focused on studying factors influencing the health of people with HIV. The K99 Phase of the award period will be completed at the Johns Hopkins Bloomberg School of Public Health. Dr. Zalla’s long-term career goal is to design and conduct rigorous epidemiologic research that addresses the health of people living with HIV. This award will allow her to gain expertise in how neighborhood conditions shape population health, and in methods for evaluating the effects of economic interventions. She will apply these skills by studying the effects of neighborhood economic conditions on care continuum outcomes among people with HIV. The study will be nested in the Johns Hopkins HIV Clinical Cohort (JHHCC), a cohort of individuals receiving HIV care at the Bartlett Clinic. The study will address the following specific aims. Aim 1: Describe the association between neighborhood economic conditions and care outcomes among participants in the JHHCC. To accomplish this aim, individual-level measures of retention in care, viral suppression, and mortality will be linked to area-level measures of neighborhood economic conditions. Aim 2: Estimate the causal effects of residential stability and residential relocation on care outcomes among participants in the JHHCC. To accomplish this aim, propensity score matching will be used to estimate the average causal effects of different residential trajectories on care outcomes. Aim 3: Quantify the impact of public and private investments in neighborhoods on care outcomes among participants in the JHHCC. This aim will use a comparative interrupted time series design and g-methods to estimate the causal effects of investments by public and private entities. This project will further our understanding of how neighborhood economic conditions affect the health of people with HIV. In doing so, it will generate evidence that directly informs the clinical care and supportive services provided to people with HIV, reduces the onward transmission of HIV, and furthers our goal of Ending the HIV Epidemic.

NIH Research Projects · FY 2025 · 2024-07

The applicant, Ms. Mia Campbell, proposes to investigate the complex relationships between caregiver experiences of unfair treatment, environmental characteristics, and adolescent depression, addressing a critical need in public health. This dissertation project will ultimately prepare the applicant for an independent research career focused on improving the prevention and treatment of depression and mood disorders among adolescents. Adolescent depression is a pressing public health concern in the United States. The significance of this research lies in the increasing prevalence of adolescent depression and its profound and long-lasting consequences on individuals' lives. Utilizing a unique dataset from the Environmental Influences on Child Health Outcome (ECHO) Program, we will apply innovative methodologies to unravel these intricate connections. In Aim 1, we will identify latent classes of caregivers based on their experiences of unfair treatment and explore their associations with adolescent depression. This study extends the existing body of research by incorporating caregiver experiences as a crucial factor in understanding adolescent depression. Aims 2 and 3 will assess the moderating effects of psychosocial and environmental factors on the relationship between caregiver experiences and adolescent depression. Employing linear mixed models, we will examine the dynamic interplay of these variables over time. We will also investigate the influence of multiple psychosocial and environmental factors to explore how they shape the relationship between caregiver experiences and adolescent depression. By adopting a transdisciplinary approach and collaborating with experts in latent class analysis, longitudinal methods, and social science scholarship, this research seeks to provide novel insights into the determinants of adolescent mental health. Our ultimate goal is to develop a comprehensive framework that integrates social and physical environments, caregiver experiences, and adolescent depression. The outcomes of this research will guide targeted interventions and policies to create healthier and more supportive environments for adolescents. In summary, this study will contribute to advancing the field of public mental health by bridging existing gaps in knowledge and practice. It will provide innovative solutions for addressing the mental health needs of adolescents and help reduce differences in depression rates, ultimately improving the well-being of the next generation.

NIH Research Projects · FY 2026 · 2024-07

Abstract: We and others have shown that AAV vectors have great potential as gene therapeutic agents (3-5), in particular for CF. Studies originating from our group led to the first use of rAAV in humans (7). Many pre- clinical and clinical trials have shown that AAV vectors can be used safely (5,6,9). The major challenge, however, is that they have not achieved a reproducible therapeutic effect, making it necessary to take a new approach to AAV gene therapy. In previous work, we have identified three new strategies to alleviate these problems: 1) the use of AAV1, which is more tropic for the lung; 2) use of 27-264, a truncated version of CFTR that corrects F508 by a novel mechanism; and 3) inclusion of a powerful chicken β-actin (CBA) promoter. Recent advances have been made in developing corrector and potentiator compounds to rescue and activate F508-CFTR (8). How- ever, although rescuing F508-CFTR would benefit many CF patients, there are more than 1000 other mutations in the CF gene (http://www.cftr2.org/), many of which create mutant proteins that are not repairable by the same compounds that rescue F508. These limitations in rescuing F508-CFTR and other mutant CFTR molecules make it even more important to develop a gene therapy for CF to treat all patients with CF. To further explore the potential usefulness of gene therapy for CF, we will use Rhesus macaques to explore the toxicology and pharmacology of AAV1-CBΔ27-264. We will use a ferret model bearing the F508 mutation to evaluate rescue of the CF phenotype in a large animal model. This model is ideal for our studies because ferrets show a tropism for AAV1 similar to that of humans and monkeys (9), and the disease phenotype can be switched on and off following application or cessation CFTR corrector/potentiator treatment. Finally, we will conduct a phase I clinical trial in patients bearing the F508 mutation. We propose three overall Specific Aims: Aim I: To evaluate single-dose administration of AAV1-Δ27-264CFTR to Rhesus macaques. Aim 2: To determine the therapeutic effects of AAV1 vectors containing truncated CFTR in F508-del Ferrets. Aim 3: To determine whether dosing with an AAV1 vector containing a truncated CFTR will lead to transduc- tion in ferret and human primary airway cells. The overarching questions for CF gene therapy are whether gene transduction can rescue the CF phenotype and how long the therapeutic effect will last before a repeated administration is necessary. The answers to these practical questions have enormous clinical consequences for the development of effective CF gene therapy. This application will address the extent to which an AAV1 vector containing AAV1-CBΔ27-264 will be effective in rescuing the CF phenotype and how long the rescue will last. Significance: CF is an autosomal disease that leads to significant morbidity and mortality in patients with the disorder (10). The work is significant because it will address the safety and efficacy of CFTR delivery via AAV1 viral vectors to lung and to demonstrate CFTR expression.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Translation is a dynamic and energetically demanding fundamental process requiring numerous factors that promote and regulate protein synthesis. Dysregulation of translation often occurs in many human diseases. For example, many pathogens promote their own replication by targeting these translation factors, the ribosome, and regulatory mechanisms to undermine translation in their host cell. One such bacterium is Legionella pneumophila, the causative agent of the severe pneumonia called “Legionnaires’ disease”. The incidence of Legionella infections in the United States has increased in recent years, necessitating a better understanding of how this bacterium interacts with its host cell. Legionella translocates hundreds of toxic proteins, termed effectors, that subvert many biochemical processes within its host. Notably, at least eleven of these effectors inhibit translation. These effectors exert their function through a range of mechanisms, and most appear to be enzymes that modify translation factors to inactivate them while others mark proteins for degradation. Despite several studies describing the mechanisms of some of these translation-inhibiting effectors, it is unclear why Legionella employs them. This is driven by the fact that the mechanisms of some effectors remain elusive but also because their seemingly redundant nature has made it difficult to isolate their physiological relevance. This proposal seeks to close the gaps in knowledge regarding the translation-inhibiting effectors by using both specific and broad approaches. First, I will determine the mechanism of one of these effectors, SidL. Based on strong preliminary data, I propose a set of experiments to characterize its function and identify its molecular target. Second, I propose a comprehensive temporal analysis of translation inhibition during the Legionella infection cycle. Legionella has a ~24-hour infection cycle and some studies suggest that the translation-inhibiting effectors are temporally regulated; however, a careful characterization of when each effector works precludes a deeper understanding of them. Together, these two approaches will establish a framework to understand the physiological relevance of the translation-inhibiting effectors of Legionella. Furthermore, because these effectors target host cell factors, this work can reveal novel insights into our own cell biology.

NSF Awards · FY 2024 · 2024-07

NON-TECHNICAL SUMMARY: Many elements play essential roles in the advancement of technology. Critical elements, including rare earth metals, are vital for electronics, renewable energy, and advanced materials. However, the stable supply of these elements remains a challenge due to the limitations of the current extraction and separation methods that are high-cost, polluting, and/or geographically constrained. Nature has evolved sophisticated metal-binding peptides (MBPs) that selectively recognize and bind certain ions and molecules, which show great promise as a new modality for critical element separation. In practice, these MBPs need to be immobilized in a porous scaffold to facilitate the adsorption of targeted elements and promote the recycling of MBPs. The goal of this project is to study and develop a new class of immobilization substrates, namely mesoporous protein crystals, for critical element separation. Protein crystals show several appealing properties for MBP immobilization, including appropriate pore size and distribution, structural stability, and low toxicity, but they are limited by a low propensity of crystal nucleation. In this project, computationally designed protein crystals will be used to study the nucleation and growth behaviors of protein crystals. The structure-property relationship of protein crystals will be systemically characterized. The team will further evaluate immobilization strategies to maximize the density of MBPs in crystals while maintaining a sufficient porosity for ion diffusion. The capability of immobilized MBPs in sequestering critical elements will be evaluated and compared to the free MBPs. The success of the project will create a new MBP immobilization platform for efficient and selective critical element separation. The platform can be generalized to immobilize other materials for broader applications. Additionally, the project will provide valuable training and education opportunities to graduate, undergraduate, and high-school students by developing educational modules on advanced biomaterials for energy and sustainability. TECHNICAL SUMMARY: This project aims to obtain a comprehensive understanding of protein crystals as immobilization substrates for critical element separation. The team will combine protein engineering and rational design to tune the assembly of protein crystals and unravel factors that impact the crystal nucleation and growth. Batch crystallization will be exploited for the scalable synthesis of protein crystals and their physicochemical properties in varied structures and binding affinity will be systemically investigated. The team will explore immobilization strategies that can maximize the gravimetric ratio of guest MBP proteins in the crystalline scaffold while maintaining stable immobilization without gradual loss of MBPs over time. The immobilization platform will be examined by immobilizing Lanmodulin (LanM), a protein derived from nature for selective sequestration of rare earth elements (REEs). The capability of LanM-crystal complexes in binding REEs and their selectivity over other bivalent and trivalent cations will be evaluated. The team will further test the performance of immobilized LanM in practical REE extraction scenarios, such as extraction from simulated low-grade leachate using fixed-bed columns packed with LanM-crystal complexes. The new immobilization platform will address the scalability, cost, and stability issues of protein-based adsorbents that traditionally hinder their deployment. The success of this project will also offer a secure and resilient critical elements supply chain essential to economic prosperity and national defense. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

HMGA1 Chromatin Regulators in Pancreatic Carcinogenesis ABSTRACT Background: We propose to elucidate mechanisms mediated by High Mobility Group A1 (HMGA1) chromatin regulators in pancreatic carcinogenesis. Pancreatic ductal adenocarcinomas (PDAC) are highly lethal cancers characterized by invasive tumor cells and a dense desmoplastic stroma. HMGA1 gene expression is activated during embryogenesis, but silenced postnatally in most adult, differentiated tissues. In diverse, cancers, such as PDAC, HMGA1 becomes re-expressed where high levels portend adverse outcomes. HMGA1 the role of HMGA1 in pancreatic carcinogenesis is only beginning to emerge. Here, we focus on actionable pathways downstream of HMGA1 as novel therapeutic targets in PDAC. Our scientific premise that HMGA1 drives tumor progression in PDAC is based on the following preliminary results: 1) HMGA1 is highly overexpressed in PDAC where high levels predict decreased survival, 2) As we recently published (JCI, 2023), silencing HMGA1 blocks diverse oncogenic properties in PDAC cell lines while depleting tumor-initiator cells in xenografts, 3) In KPC mice with PDAC driven by mutant Kras and Tp53, deficiency of HMGA1 disrupts tumorigenesis while prolonging survival. 4) Surprisingly, loss of just a single Hmga1 allele within the pancreatic epithelium is sufficient to impair both tumor and stroma formation in KPC mice, 5) Mechanistically, HMGA1 functions as an epigenetic switch by activating transcriptional networks involved in proliferation and oncogenic transformation in PDAC cell line models, including the FGF19 growth factor gene, 6) Targeting FGF19 gene expression or function by FGFR4 receptor blockade in xenograft models disrupts tumor and stroma formation, 7) Most importantly, tumors with high expression of both HMGA1 and FGF19 define a molecular subclass of human PDAC with exceptionally poor outcomes. 8) In KPC mice, Hmga1 deficiency within pancreatic epithelium results in increasing immune cell infiltration in pancreatic tumors, suggesting that HMGA1 also drives immune evasion by Together, these intriguing results support the following hypotheses: 1) HMGA1 is required for PDAC progression and stroma formation through epigenetic alterations and gene networks that foster aberrant proliferation, differentiation, and TME signaling. 2) HMGA1 within tumor cells modulates the TME to promote immune evasion, 3) Targeting pathways governed by HMGA1 will provide novel therapeutic strategies. Aims/Approach: To test this, we propose the following Specific Aims: 1) To precisely define HMGA1- dependent mechanisms in tumor progression using KPC mice and primary human tumors, and, 2) To test targeting HMGA1 pathways for therapeutic efficacy in preclinical models. Impact: This work should reveal new paradigms for PDAC pathogenesis and lead to novel approaches to treat, or even prevent, these profoundly recalcitrant tumors.

NIH Research Projects · FY 2025 · 2024-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The otolaryngology specialty requires a wide variety of expertise and scientific strategies for understanding and treating communication disorders. Our program’s goal is to train and develop physicians who will advance the field of otolaryngology and serve as its future innovators and leaders. We aim to provide a solid foundation for medical student and resident participants’ futures in otolaryngology research by 1) providing tailored mentored research experiences for otolaryngology residents and medical students interested in matching with otolaryngology residency programs; 2) leveraging our cross-disciplinary institutional resources to provide professional development training and research skill-building to prepare participants for clinician-scientist careers; and 3) enhancing recruitment of individuals with primarily clinical backgrounds to careers in otolaryngology research. We will provide the research training, communication, and professional skills that will enable our graduates to become creative contributors to the future of otolaryngology and the treatment of associated communication disorders. Two residents per year will enter into 18 continuous months of research training in their third year of residency. Additionally, 2 medical students per year will be recruited for 9 months of research training. These students will be paired with near-peer resident mentors. These trainees can choose from a wide and deep selection of research themes both within the department and in associated laboratories at Hopkins and elsewhere. Mentoring teams will include preceptors and co-preceptors with a history of training clinician- scientists and early healthcare professionals, academic achievement, and competing for research funding. Research topics include, but are not limited to: basic mechanisms of, and therapeutic innovation for dizziness and balance; studies of the auditory nervous system; pathogenesis of sinusitis, laryngotracheal stenosis and respiratory papillomatosis; outcomes, quality and safety in otolaryngology; molecular biology and epidemiology of head and neck cancers; surgical robotics; and public health studies in otolaryngology-head and neck surgery. Program participants will benefit from access to state-of-the-art research facilities, a highly collaborative research environment representing a variety of disciplines, and substantial institutional resources. Participants will also complete a curriculum focused on safety and compliance, rigor & reproducibility, research skill-building, grantsmanship, laboratory management, and navigating careers as clinician- scientists. The program will build upon 33 years of successful research training in our T32 program, which has produced many clinician-investigators and leaders in otolaryngology-head and neck surgery.

NSF Awards · FY 2024 · 2024-07

The National Science Foundation (NSF) has named Dr. Muyinatu Bell as the 2024 recipient of its Alan T. Waterman Award. This award is NSF's highest honor that annually recognizes an outstanding researcher age 40 years or younger and funds his or her research in any field of science or engineering. This year's awardee will receive a $1 million grant over a five-year period for further advanced study in her field. Dr. Bell is an associate professor at Johns Hopkins University, best known for inventing the short-lag spatial coherence (SLSC) ultrasound beamformer, which significantly improves ultrasound image quality by reducing acoustic clutter. She has also adapted the SLSC technology to photoacoustic imaging, most recently using it to overcome problems related to skin tone bias. Dr. Bell is a lecturer, mentor and scientific role model committed to engaging a diverse research community by serving in leadership roles on committees and programs aimed at supporting women in physics, computer science and engineering. She is the recipient of NSF awards from the Faculty Early Career Development (CAREER) program and the Smart Health program. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

Project Summary: Long COVID impacts 10-30% of people after a SARS-CoV-2 infection, with potentially devastating long-term impact on quality of life. Moreover, Long COVID disproportionately affects minority, rural, older, and other at-risk populations. Multidisciplinary Long COVID clinics provide clinical care and offer infrastructure for evaluating promising interventions to improve Long COVID outcomes. The Johns Hopkins Post-Acute COVID-19 Team (JH PACT) is among the country's first and largest Long COVID programs. Via this AHRQ U18 proposal, JH PACT proposes the following Aims: (1) To deliver a comprehensive, multidisciplinary program (Supporting Patients Recovering from COVID, “SPaRC”) to patients with Long COVID, with an expanded focus on underserved populations. The SPaRC program will expand on the existing expertise of the JH PACT multidisciplinary Long COVID outpatient program to increase capacity and decrease wait times, with expanded services to underserved patient populations, including older adult, minority race/ethnicity, socioeconomically disadvantaged, and geographically distant and rural populations via enhanced partnerships with key existing organizations (e.g., Medicine for Greater Good, Center for Clinical Global Health Education). (2) To iteratively evaluate and refine the SPaRC Long COVID program to increase access and improve patient-centered, evidence-based care. The SPaRC program will be evaluated and iteratively refined in quarterly cycles via mixed methods evaluation (via patient data from electronic medical records and semi-structured qualitative interviews of patients/caregivers and staff/clinicians) to inform implementation strategies based on the “Expert Recommendations for Implementing Change” (ERIC) framework within a learning health system. In each review cycle, the implementation team and key SPaRC internal and external stakeholders will evaluate the program and outcomes and select goals for refinement and advancement for the next quarterly review cycle. An external Stakeholder Advisory Council, led by an independent Chair, will provide ongoing feedback via quarterly meetings throughout the project. (3) Partner with regional Long COVID stakeholders, including primary care providers (PCPs), to create and expand access to comprehensive, patient-centered, coordinated Long COVID care across the mid-Atlantic region. We will build a multi-disciplinary Long COVID provider-to-provider e-consult service, customized educational curriculum (delivered via both live and on-demand electronic formats), and continuing education toolkit for PCPs, in conjunction with key stakeholders (e.g., patients, caregivers, community leaders, and PCPs). JH PACT and the SPaRC Team include internationally-recognized experts in Long COVID care, patient outcomes assessment, implementation science, stakeholder/community engagement, and primary care education. JH PACT is ideally positioned to create a Long COVID Center of Excellence, leveraging the outstanding expertise available via Johns Hopkins Medicine, and to optimally engage with the AHRQ Learning Community.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT Indigenous peoples in the United States and worldwide face the starkest inequities in premature mortality of any racial and ethnic group. In the United States, American Indian/ Alaska Native (AI/AN) Peoples have 2X higher rates of suicide, 4X higher rates of alcohol induced deaths, and 1.6X higher drug overdose deaths compared to the US general population. To effectively drive change in the staggering inequities, we need a scientific workforce that better represents Indigenous peoples. To date, Indigenous and other diverse scholars are vastly underrepresented in NIH funding, including fellowship and training grants. The parallel inequities in public health education, training, and preventable cause mortality stem from historical and contemporary social and structural determinants. The goal of the Elevating Indigenous Wellbeing through Assets-Based Prevention Science (ELEVATE) Training Program is to train Indigenous and other diverse predoctoral scholars to become leaders in health equity research and strengths-based multi-level prevention science, addressing worsening inequities in mental- and behavioral-health-related premature mortality among Indigenous Peoples. To accomplish this goal, we will provide rigorous training and high-quality mentorship in (1) Health disparities/health equity research, (2) Developing and implementing multi-level prevention interventions, and (3) Methods to design and analyze studies that evaluate multi-level prevention interventions. We will also provide cross-cutting training in (4) Indigenous methodologies as a way to root this training and decolonizing approaches. Trainees well benefit from the program’s interdisciplinary and team-based mentorship and training approach. The ELEVATE program will he led by a team of Indigenous and allied leaders and leverage the vast resources of the Johns Hopkins Blumberg School of Public Health, including the Center for Indigenous Health’s (CIH) 40+ year trust-relationships with Tribal Nations and growing number of Indigenous and allied faculty. Specifically, the ELEVATE program will be housed in the Social and Behavioral Interventions program, but the 3 trainees per year may also come from the Department of Mental Health or full-time students from the school wide Doctorate of Public Health Program. Trainees well undertake a rigorous program of coursework in health equity, multilevel prevention, and associated and Indigenous methodologies. A year-long seminar to discuss research in progress, ongoing mentored research projects, and integrative activities will complement coursework. ELEVATE will synergize with CIH’s NIDA-funded P50 National Center for Excellence, Community-Driven Indigenous Research, Cultural Strengths & Leadership to Advance Equity in Drug Use Outcomes (CIRCLE). This proposed program aligns directly with the goal of the ADVANCE Predoctoral T32, the cross-cutting themes for the Office of Disease Prevention’s strategic plan, and would address key cross-cutting strategic priorities for NIDA, NIMH, and NIAAA. There are currently no predoctoral training programs for Indigenous health. The ELEVATE program fills this gap and will help build the next generation of Indigenous and other diverse prevention scientists.

NIH Research Projects · FY 2025 · 2024-07

Project abstract There are two main objectives for this 5-year career development plan: 1) define the role and mechanistic basis of skeletal muscle actin mutations in dilated cardiomyopathy (DCM), and 2) transition the principal investigator (PI) to independence through professional and scientific mentorship. Despite current therapies, many patients with DCM progress to end stage heart failure possibly due to a lack of treating changes in contractility which needs further exploration. The basis of all contraction in cardiac and skeletal muscles is myosin pulling on actin filaments. Skeletal muscle actin is the minor actin isoform in the heart, and it has never been mechanistically explored in DCM. In this proposal, the PI establishes a multiscale experimental platform that utilizes biochemical, biophysical, and in vivo methods to robustly study the effects of the skeletal muscle actin mutation R256H on heart and skeletal muscle. The PI previously found that R256H exceptionally associates with DCM without skeletal myopathy unlike all other skeletal muscle actin mutations. His preliminary data demonstrates that R256H has a dominant negative effect on contractility only in the presence of the actin-binding proteins troponin and tropomyosin which is a novel mechanism that was discovered using a new technique of recombinant actin purification created by the PI. He also establishes that R256H causes hypcontractility in human cardiomyocytes and mouse hearts. He hypothesizes that R256H causes DCM without skeletal myopathy due to tissue-specific expression of different isoforms of troponin and tropomyosin. This hypothesis will be tested by elucidating the biochemical and structural effects of R256H in the context of cardiac and skeletal muscle troponin and tropomyosin (Aim 1), defining the effects of R256H on cardiac and skeletal muscle cells and engineered tissues (Aim 2), and analyzing the effects of R256H on cardiac and skeletal muscles of mice (Aim 3). Completing these aims will establish the role of skeletal muscle actin mutations in DCM for the first time and create a multiscale platform to study additional skeletal muscle actin mutations in cardiomyopathy for the PI’s first R01. Moreover, with guidance of a formal mentoring committee, the PI will complete a curriculum that will build his biochemistry and biophysics knowledge and techniques, teach him cryoEM structural analysis to connect structure to function, and expand his understanding of cardiac and skeletal muscle disease modeling in animals. Finally, he will improve his professional, logistical, and educational skills to fully transition to an independent investigator and productive member of the scientific community capable of training future physician-scientists.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY While there have been tremendous advances in the treatment of estrogen receptor-positive (ER+) breast cancer, late-stage ER+ metastatic breast cancer (MBC) has very poor prognosis. The chief reason for this is tumor endocrine resistance, wherein tumors do not respond to ER-targeting therapies. Endocrine resistance is the major reason for breast cancer mortality, and a primary challenge in the treatment of ER+ MBC. The most well known mechanism of endocrine resistance is hotspot activating mutations in ER that lead to ligand independence. These hotspot mutations are effectively inhibited by the newest class of endocrine therapy, novel oral selective ER degraders (SERDs), and serve as a biomarker for SERD responsive tumors. We found a novel non-hotspot ER variant of unknown significance, and double hotspot mutations (in cis, on the same ER molecule) from clinical whole-exome sequencing of tumors with acquired resistance to ER inhibition. These single and double mutations are frequent, with the latter present in ~5% of resistant tumors. Without preclinical characterization, these variants represent an unknown entity in terms of biology and therapy response. In pilot studies, we found they confer strong resistance to select ER and CDK4/6-targeting therapies, and that structure modeling suggests they are predicted to alter ER binding to its ligand, inhibitors, and/or transcriptional co-factors. Robust preclinical studies in well-established models of breast cancer are required before these findings can be translated to the clinic. In this application, we propose comprehensive preclinical characterization of these prevalent novel ER variants through two specific aims: 1) assess oncogenic potential and downstream signaling by novel ER variants, specifically to determine how they dysregulate downstream ER transactivation, through transcriptomic, epigenomic, and proteomic profiling, reporter assays, and structure modeling, and 2) profile their response to targeted therapies in cell line, patient-derived organoid, and animal xenograft models. At the end of the grant term, we expect to a) validate novel ER variants as potential biomarkers that may predict resistance to ER and CDK4/6 inhibitors, particularly the novel SERDs, b) identify the structural basis by which these novel variants, and particularly, double hotspot mutations dysregulate ER, and c) identify potential targetable nodes for tumors that acquire these novel ER mutations. Our results would help design clinical trials to overcome resistance, and that may avoid unnecessary additional burden of toxicity in heavily pre-treated patients. Developing biomarkers that predict response to oral SERDs will also enable the stratification of patients whose tumors express these novel ER variants onto alternate therapeutic regimens without delay (precision medicine). These studies have strong potential to reduce the mortality associated with breast cancer, and are thus, well-aligned with the mission of the NCI.

NIH Research Projects · FY 2025 · 2024-07

SUMMARY Glaucoma is a leading cause of blindness in the United States and worldwide. The disease is characterized by the death of retinal ganglion cells after the initial injury to their axons in the optic nerve head and by extensive changes in the structure of the connective tissues of the optic nerve head. There is consensus that the intraocular pressure generates a biomechanical response in the tissues of the optic nerve head that is fundamental to the development of glaucoma axon damage. Mechanical deformation and remodeling of the optic nerve head in response to a long-term IOP elevation can damage the retinal ganglion cell axons both directly and indirectly through mechanical activation of the astrocytes and lamina cribrocytes and disruption of blood flow from the distortion of blood vessels. The cells of the optic nerve head can also react to changes in the mechanical properties of the connective tissue structures of the optic nerve head in ways that compromise the physiological support for the axons. The scientific premise of the proposed study is that biomechanical behaviors and properties of the tissues of the optic nerve head will predict the risk of axon injury in open angle glaucoma. In Aim 1, we will image the eyes of human subjects with primary open angle glaucoma at different stages using an optical imaging method called spectral domain optical coherence tomography. Images will be acquired before and after a change in the intraocular pressure to measure the deformation using digital volume correlation. The IOP will be changed by laser suture lysis as part of the post-operative care of patients who have had recent trabeculectomy surgery and by starting or stopping glaucoma medication. In Aim 2, we will develop patient-specific finite element models. The models will be used to analyze the deformations measured in Aim 1 to determine the patient-specific mechanical properties of the tissues of the optic nerve head. The mechanical properties and strains will be analyzed to determine how they vary with age, sex, race, stage of glaucoma damage, and the rate of past progression. In Aim 3, we will analyze the outcomes in Aims 1 and 2 to identify potential biomechanical markers for prospective longitudinal studies to evaluate the ability of the biomechanical markers to predict glaucoma progression. We will also reimage the eyes of participating patients to measure remodeling to the structure and mechanical properties of the optic nerve head. These studies will determine whether the deformations and material properties of the tissues of the optic nerve head, measured by current imaging, image analysis and modeling methods, are predictive of glaucoma progression and enhance fundamental understanding of how the tissues remodel in open angle glaucoma.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Sale of cannabis for recreational use is rapidly becoming legal across states in the US. While cannabis use policies typically contain marketing restrictions, including prohibitions on misleading marketing claims, there is limited research to inform operationalization of these policies, and these policies are rarely enforced. Cannabis products are often labeled based on “species” or cultivar (Indica, Sativa, or Hybrid). Notably, there is limited evidence that different species consistently have different profiles of chemical constituents. Despite this, cannabis is marketed directly to consumers with product labels “Indica”, “Sativa”, and “Hybrid”, and with corresponding marketing claims that the product has sedative (e.g., relaxation, sleepiness) or energizing (e.g., focus, productivity, physical activity) effects. Consumers also report experiencing sedative effects from Indica- labeled cannabis and energizing effects from Sativa-labeled cannabis. This may translate into unsafe use: our prior work has found consumers are more likely to report using Sativa-labeled (vs. Indica-labeled) cannabis before driving or going to work. Despite the potential for public health harm, there is no data demonstrating whether product perceptions, use expectancies, and subjective and objective acute effects of use vary by label or marketing claim. Research from other consumer domains, including tobacco, indicates that labeling and marketing can have powerful effects on product perceptions, use behavior, and use experience. Marketing and labeling for cannabis could similarly foster inaccurate product perceptions (e.g., regarding harm), expectancy effects (e.g., anticipating a product to increase focus) and lead to unsafe use (e.g., while driving). This undermines initiatives to promote safe use of cannabis and risks public health. To date, controlled research has not systematically evaluated how product labeling (Indica, Sativa, Hybrid) or associated marketing claims (sedative vs. energizing) affect use behavior, risk perception, or acute drug effects. The proposed research uses a large-scale content analysis of cannabis labeling and marketing (Aim 1), a randomized online experiment (Aim 2), and a placebo-controlled randomized laboratory experiment (Aim 3) to document the scope and effects of cannabis labeling (Indica, Sativa, Hybrid) and marketing claims (sedative, energizing). Ultimately, this work will provide evidence to inform cannabis marketing and labeling policies, which are necessary to protect public health.

NIH Research Projects · FY 2024 · 2024-07

Project Summary This is a resubmission (original December 2022). Work on SA1 and didactic training is underway. Demand for intensive care unit (ICU) beds in the United States is high and frequently exceeds supply. This leads to delays or denials of ICU admission, which are associated with increases in patient morbidity and mortality. In over 60% of US hospitals, intermediate care (i.e., step-down care, progressive care) is an alternative to intensive care for some patients. While the organization, provider staffing models, and monitoring and interventions available in Intermediate Care Units (IMCUs) varies, a consistent feature distinguishing intensive care, intermediate care, and acute ward care is the nurse-to-patient ratio (NPR). Whereas the standard NPR in the ICU is 1:1 or 1:2, it is usually 1:3 in IMCUs, and 1:5 or 1:6 on acute care wards. These different ratios reflect an assumption that intermediate care is associated with less workload per patient than ICU patients, and more than ward patients. However, there are concerns that nurse workload in some models of intermediate care exceeds that of ICU nurses. Importantly, excessive workload is tightly linked to increased patient morbidity and mortality, low nurse job satisfaction and high burnout. It is essential to understand what features of intermediate care nursing work modify (e.g., amplify or decrease) workload in different models of intermediate care. In this mixed methods proposal, we will conduct in-depth qualitative assessments to identify performance shaping features (PSFs) of intermediate care nursing work. These qualitative assessments are guided by the Systems Engineering Initiative for Patient Safety (SEIPS) conceptual framework, a well- established human factors engineering approach, to guide ethnographic observations, semi-structured interviews, and focus groups of intermediate care nurses to identify PSFs that amplify or decrease nursing work. We will then conduct a quantitative assessment to characterize the strength of association between these PSFs and perceived nursing workload among intermediate care nurses in the Johns Hopkins Health System (JHHS). Perceived nursing workload will be measured using the National Aeronautics and Space Administration Task Load Index (NASA-TLX), a short (< 5 minute) and well validated measure (in many work systems including nursing) of perceived workload. This proposed research and training, including didactic instruction in statistics, epidemiology, human factors engineering, qualitative methods, and survey design will provide the applicant with the experience and skill needed to continue his professional goal of becoming an independent investigator studying intermediate and critical care delivery within health systems. These findings will provide important insight into planning and supervising this level of care and will provide preliminary data for a planned K23 proposal to be submitted in his fourth year of fellowship.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY The glucocerebrosidase 1 (GBA1) gene is the most common genetic risk factor for Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). The L444P mutation is the most frequent occurrence and is known to cause early onset and severe forms of PD and DLB. A deficiency in the functional enzyme, GBA1, occurs in lysosomes due to misfolded GCase not properly transferring to the lysosomes and instead being retained in the ER. The accumulation of misfolded mutant GCase leads to ER stress, which in turn causes GCase to move to the cytoplasm and interact and stabilize soluble α-synuclein (α-syn) oligomers. This accelerates the formation of pathological α-syn in PD pathology. The evidence linking GBA1 mutations to PD and DLB has sparked interest in researching GCase as a target for therapy. Enzyme replacement therapy is the most commonly used approach, but it has limitations in crossing the blood-brain barrier. Substrate reduction therapy has also seen limited success in clinical trials. An alternative approach, using molecular chaperones to aid the misfolded GCase and increase its translocation to lysosomes, has gained attention. This has led to the screening of both pharmacological and small molecule chaperones for their ability to cross the blood- brain barrier, making it a promising therapeutic strategy for PD and DLB. Discovered chaperones, both inhibitory and non-inhibitory, through high-throughput screening (HTS) have demonstrated an improvement in GCase activity, however, many have failed to be effective in clinical trials. This may be due to the limitations of the model used for screening. The use of recombinant wild-type GCase and patient-derived fibroblasts that do not accurately represent the mutant protein, as well as the tissue-specific expression of the protein to reflect disease pathology, has limitations. HTS using patient-derived iPSCs can provide more accurate results, but it is a labor-intensive and costly process to screen large libraries. To address these challenges, we have devised an economical genetic model that employs low substrate concentration in SH-SY5Y cells carrying the L444P mutation. This is supported by a platform that integrates fluorescence-based assay and flow cytometry to assess GCase activity. In Aim 1, we will perform an initial screening of 11,280 small molecule compounds to boost GCase activity using the SH-SY5Y GBA1L444P/L444P and GBA1L444P/+ cell lines. Additionally, our aim is to select the top 5 hit compounds through secondary screening of the top 10. In Aim 2, we will assess the efficacy of these 5 hit compounds in alleviating the disease symptoms in human dopaminergic (hDA) neurons with GBA1L444P/L444P mutation. We will prioritize assessing the efficacy of the top five hit compounds in rescuing impaired differentiation of neuronal progenitor cells with the GBA1L444P/L444P mutation into hDA neurons considering the time and budget constraints of the R03 award. This research will lead to the identification of innovative drug candidates for treating GBA1-related PD/DLB and sporadic PD/DLB, and it will also offer a new platform for drug screening for patients with this condition.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract There is increasing evidence over the past decade that the composition of the gut microbiome is important for cancer therapy effectiveness including chemotherapy, endocrine therapy, and immune therapy. In fact, modulation of the microbiome is in clinical trials to enhance immunotherapy clinical responses in multiple solid tumors. Despite the explosion of studies on the microbiome-cancer therapy axis, relatively little is known about the mechanism(s) utilized by gut microbiota to shape therapy response or resistance. In metastatic castration resistant prostate cancer (mCRPC), the deadly form of the disease, intra-tumoral androgens likely mediate immunotherapy and endocrine therapy resistance. Collectively, the three PIs of this application have 1) identified and characterized the only known human-associated bacterial genes capable of converting glucocorticoids into non-conventional androgens; 2) collected and sequenced a 5-year microbiome biorepository from individuals with advanced prostate cancer taking oral androgen axis-targeted therapy; and 3) demonstrated that response to immunotherapy in advanced prostate cancer requires androgen receptor inhibition on T cells. Working together, we provide evidence that species of the gut microbiome produce androgen metabolites that act as ligands for the androgen receptor. This observation underscores our clinical observation that the gut microbiome of endocrine therapy or immunotherapy sensitive versus resistant patients is distinct and significantly unique. We propose that androgen metabolism by the gastrointestinal (GI) microbiota serves as a unique source of tumor-associated androgens that promote endocrine and immune therapy resistance. We propose the following aims: Aim 1: Define the functional significance of microbial-derived androgens on immunotherapy effectiveness. We will determine if microbial-derived androgens are sufficient to mediate therapy resistance and how these metabolites regulate murine and human T cell function. Aim 2: Determine the GI microbial gene pathways and androgen metabolites that are determinants of therapeutic response and resistance in mCRPC. These studies will identify novel bacterial species and genes associated with endocrine and immunotherapy resistance. Aim 3: Evaluate the impact of microbial-derived androgen production on tumor intrinsic growth, MHC I expression, and abiraterone acetate/prednisone resistance. We will evaluate the cause-and-effect relationship between microbial metabolism of androgens and endocrine therapy resistance. Cumulatively, these studies provide a mechanistic understanding of how the human microbiome promotes endocrine resistance and inhibits anti-tumor immunity and provide novel microbiota-associated therapeutic targets to reduce androgen-mediated immune suppression.

NSF Awards · FY 2024 · 2024-07

This award funds a conference to bring together Future Manufacturing (FM) grantees and program officers from the National Science Foundation (NSF), and other federal agencies as appropriate. FM was created to support fundamental research, education, and training of a future workforce to catalyze the development of new and innovative manufacturing capabilities that do not exist today. FM aims to promote US leadership in advanced manufacturing, and enable advances in the fields of cyber-, eco- and biomanufacturing. This conference brings together FM awardees to foster engagement within the advanced manufacturing community across multiple domains including academia, industry, and government, to highlight progress in diverse areas of research, to identify new collaborative endeavors, and to address future grand challenges in the field. The following topics will be discussed throughout the conference: 1) Advanced Manufacturing Technologies, 2) Building Resilience into Manufacturing, 3) Translation into Commercial Sectors, 4) Sustainability in Manufacturing and 5) Education and Training Initiatives and Broader Impacts. A primary goal of this conference is to assess the current status and opportunities for FM across the US. Aims being pursued at this event include: 1) bringing together FM investigators to report on current project findings to date in partnership with the NSF, 2) interacting with other FM awardees to identify synergies and collaborations, 3) identifying methods to transition successful FM projects into the marketplace, 4) developing practices to expand workforce participation in diverse and inclusive environments. The conference will include oral sessions on FM-related activities and topics, breakout sessions on broad topics of common interest, and poster sessions outlining research advances by PIs. Results from the conference will be published for the FM research and broader community via a Conference Proceedings that will include a compilation of project abstracts. The conference will be held in downtown Washington DC 1-2 August 2024. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

Meibomian gland disease (MGD) is considered the leading cause of dry eye disease, a common multifactorial disease with a global prevalence of 5 to 50% and a major age-related disease of the ocular surface. Meibomian glands (MG) are modified sebaceous glands that line the margin of the eyelid, secrete lipids at the ocular surface, and participate in increasing the stability of the tear film. MGs are holocrine glands, which implies they are continually renewed since they deliver their secretory product, called meibum, by apoptosis. Thus, regulation of MG stem cells is crucial to ensure the proper function of MGs. With the aging process or disease condition, MGs can progressively lose their renewal capability and regress to an atrophic state. The pathogenesis of MGD and the mechanisms by which aging affects the renewal process remain largely unknown. Treatment options are currently limited mainly due to the lack of clear therapeutic targets and effective drug delivery strategies targeting the tissue of MGs. Thus, there is a critical need to understand signaling cascades underlying the renewal process of the MG that can be pharmacologically targeted to treat MGD. Our recent advances, with the aid of an NIH/NEI R21 (EY030661), have led us to discover a novel role of the primary cilium in MG development and maintenance suggesting a role of HH in the this process. The Hedgehog (HH) pathway plays a fundamental role in tissue development, homeostasis, and repair, including adult stem cell maintenance. To determine the therapeutic potential of targeting the HH pathway to treat MGD, we will investigate its role in MG development, maintenance, and renewal and trace the cell lineage of HH-responsive cells involved in MG homeostasis. We will target the HH pathway in mice using genetic and pharmacological HH modulators to improve age-related MGD. If successful, the outcome of this work will reveal mechanistic insights into MG renewal and define a novel paradigm for how to approach novel treatment strategies for MGD.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract The overarching goal of these proposed aims is to form the Johns Hopkins-Emory-developmental AIDS research center (JH-E-dARC) focused on improving the measurement of stigma and interventions focused on responding to stigma as a threat to both mental health and suboptimal individual and population-level HIV outcomes in the US and around the world. In response, with the JH-E-dARC we aim to build capacity among emerging and established investigators globally to study public health responses to stigma. The JH-E-dARC is proposed as a partnership across the Johns Hopkins School of Public Health and the Rollins School of Public Health at Emory University, building on more than a decade of partnership in stigma and HIV research funded by the NIMH, NINR, NIAID, USAID, CDC, amfAR, and MAC AIDS Foundation. The specific aims for the JH-E-dARC are: Aim 1. Build local and global capacity to measure and respond to stigma as a risk for both suboptimal mental health and HIV outcomes (Administrative Core) The Administrative core (AC) will support center research coordination and output through efficient and effective management structures, sharing of methodological resources, and support for dissemination. The AC will provide consultative support on grant applications as well as support IRB applications through review and tracking approvals. In addition, the AC will develop and maintain the public website for the ARC to communicate the overarching scientific aims and the individual studies, disseminate results, and provide a hub of resources for stigma measurement and intervention methodology. Aim 2 Improve the measurement of stigma to better study the impact of attribute-specific and intersectional stigmas on mental health and HIV (Research Core 1) The stigma measurement core will support creating rigorous assessment strategies incorporating quantitative, qualitative, and mixed methods for collecting data to analyze relationships between stigma and mental health outcomes, including depression, anxiety, and dependency and HIV outcomes in epidemiologic and interventional studies. Aim 3 Increase the quantity and quality of interventions addressing stigma and structural determinants of risk in the domestic and global HIV response (Research Core 2) This intervention core will provide guidance on design of structural and multilevel stigma interventions and research to study those interventions, including explanatory and pragmatic experimental designs, quasi- experimental, and observational studies. Aim 4 Support the proliferation of science in measuring and responding to stigma and structural determinants of HIV among diverse emerging scientists (Developmental Core) The development core will support capacity development of emerging and established investigators by providing expert research development support, dedicated mentorship, taking an individualized approach to capacity building across partners, and by creating knowledge-sharing pathways across the center and beyond.